11 prescription (legal) status categories vary country by country np („otc”) pom subcategories...
TRANSCRIPT
![Page 1: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/1.jpg)
11
Prescription (legal) status
Categories vary country by country
• NP („OTC”)• POM• Subcategories
Prescription
![Page 2: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/2.jpg)
22
EU Directive
Main categories• NP• POM
renewable/non-renewable prescriptions
special medical prescr.
restricted medical prescr., reserved for use in spec. areas
![Page 3: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/3.jpg)
33
EU Directive
A medicinal product is NP, if it does not meet the criteria of POM
(Very important!)
(In many countries just the opposite is applied)
![Page 4: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/4.jpg)
44
EU Directive
When POM?• danger, even used correctly, if without
medical supervision• frequently used incorrectly presenting
danger• APIs with activity/ADRs still be
studied• parenterals
![Page 5: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/5.jpg)
55
EU Directive
POM, sub-category specialist’s prescription
• narcotic/psychotropic substance
• if used incorrectly, abuse/misuse
• novel active principle, precautionary
![Page 6: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/6.jpg)
66
EU Directive
POM, sub-category restricted use
• can be used in hospitals only
• can be diagnosed in hospitals only
• specialist’s supervision (e.g. ADRs)
![Page 7: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/7.jpg)
77
EU Directive
(SUB)CATEGORIZATION
• Taking into account single and max. daily doses, strength, dosage-form, pack unit
• Annually updated published list of POM (sub)categories
![Page 8: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/8.jpg)
88
EU Guideline
Goal:
To help MAHs when applying to change the classification
(i.e., to harmonize the swithches!)
• POM/NP criteria
• switch application criteria
![Page 9: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/9.jpg)
99
Guideline NP or POM?
Direct danger: even if used correctly
• Toxicity
• Serious and existing less serious ADRs
• Interactions with commonly used drugs
![Page 10: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/10.jpg)
1010
Guideline NP or POM?
Indirect danger:
• Masking conditions that would require medical attention. NP: time-limit must be set
• Wider use increase resistance, particularly in general population
![Page 11: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/11.jpg)
1111
Guideline NP or POM?
Risk and consequences of incorrect use
• If used according to indications (too many contra-indications, precautions, warnings, etc. May lead to incorrect use
• If the opposite: off-label or longer use
![Page 12: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/12.jpg)
1212
Guideline NP or POM?
Self-assessment/diagnosis• Symptoms can be correctly assessed by
patients (may vary country by country!)• Natural course of disease, duration or
re-occurrence of symptoms may be self-assessed
• Contraindications, etc. can be understood by the consumer
![Page 13: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/13.jpg)
1313
Guideline NP or POM?
• The way patient info is written
• „If not POM, must be less dangerous”
• Layman’s terms used?
• Explanation of use?
• Explanation when should not be used?
![Page 14: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/14.jpg)
1414
Good question - who is „Patient”?
![Page 15: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/15.jpg)
1515
Summarising the legal status
Ailment Treatm. ADR Dr’s diagn. Med.Att. Status
Minor any NS none no NP
Major single NS yes no NP/POM
Major long NS yes rare NP/POM
Major long S yes rare NP1/POM
Major any any yes yes NP2/POM
1if the patient can be informed…
2the smallest pack size
![Page 16: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/16.jpg)
1616
In case of rigid systems...
The NP/POM choice may cease to exist!
Rigid systems:
• Drugs are officially classified either NP or POM (NP may be prescribed but not vice versa!)
• If NP no reimbursement
![Page 17: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/17.jpg)
1717
Professional switches?
• It must be realised: this is a semi-political matter!
• If no consensus between reimbursement-policy makers and DRAs, affordability problems may occur!
![Page 18: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/18.jpg)
1818
The second issue:
OTC distribution channels in the country
and/or
![Page 19: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/19.jpg)
1919
The third issue:
Patients, their perception to medication, knowledge on drugs, etc.
(Average patient does not exist!)
![Page 20: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/20.jpg)
2020
Back to the registration: Accompanying sheets
• SmPC (Summary of Product Characteristics = Data Sheet) for professionals
• PIL for patients• Label• (Assessment
Report written by the DRA)
Medi
cine
![Page 21: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/21.jpg)
2121
Issuance of the MA
• Civil Service authoritative text (what is contained is binding!)
• The Accompanying Sheets annexed
STAMP
![Page 22: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/22.jpg)
2222
Actual marketing (in many countries)?
Pricing and reimbursement negotiations!
• MA: risk/benefit• Pricing,
reimbursement: cost/benefit
![Page 23: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/23.jpg)
2323
MA withdrawn (deletion from the Register)
• Applies to „the product”!
• Who may initiate:
• MAH - without specifying any reason (!)
• Medical Boards, DRA - with good reason (risk/benefit)
• Civil Service authoritative decision
![Page 24: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/24.jpg)
2424
Withdrawal/Recall from the market
• It applies to a given batch of the medicine!
• Decided by the DRA, MAH may initiate it
• In Hungary: DRA informs by telefax the Nat. Publ. Health Serv., and central health-care organs
• Then “info-cascade” in the counties
![Page 25: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/25.jpg)
2525
European Union
• The present marketing authorisation rules and procedures
![Page 26: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/26.jpg)
2626
Certain EU terms
• Sources of law:
Regulation
Directive
• Brussels: Commission, DGs DG Enterprise, DG SANCO
• London: European Medicines Agency (EMA)
![Page 27: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/27.jpg)
2727
EMA
• Established in 1995
• Both 2 DGs pharmacists until now
• Task: centralised MA procedure, ADR monitoring, guidance, appeal procedures
• Committees (one per member state)
![Page 28: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/28.jpg)
28
EMA Committees
• C’ttee of Human Medicinal Prodcts CHMP• C’ttee of Veterinary Medicinal Products
CVMP• C’ttee of Orphan Medicinal Products COMP• Herbal Medicinal Products C’ttee HMPC• Pediatric Committee PDCO• C’ttee of Advanced Therapy Medicinal
Products CAT
28
![Page 29: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/29.jpg)
2929
MA procedures in the EU
Procedures• Centralised CP• Decentralised DP• Mutual recognition
MRP• National
![Page 30: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/30.jpg)
3030
Centralised MA procedure
• Mandatory: biotech substances, HIV/AIDS, cancer, diabetes, neurodegenerative diseases, orphan drugs (5:100,000), somatic cell- and tissue therapy medicinal products
• Possible:
new active substances
“high-tech products”
new, “important” indication
blood products
![Page 31: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/31.jpg)
3131
Centralised procedure
• One single application to EMA• CHMP-assessment (2 rapporteurs from MSs)• 210 days dead-line, then EMA issues
Accompanying Sheets (SmPC, PIL) and Assessment Report in all languages
• MSs: 15-day possibility for „serious risk to public health” appeal
• Then signature by the Commission in Brussels: MA valid for the whole EU
• If negative: banned for the whole EU!
![Page 32: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/32.jpg)
3232
Decentralised procedure
• Possible: any product for which CP is not mandatory
• “Referens MS (DRA)”, RMS where the first application is submitted (“lead market”) and
• Concerned MS (DRA) CMS where to submit later
![Page 33: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/33.jpg)
3333
Decentralised procedure
• Application dossiers sent to RMS and CMSs, validation
• RMS: preliminary MA issued (time-frame!), Accompanying Sheets and Assessment Report (also in English)
• Discussion with to CMSs = final MA = national MAs in RMS and CMSs
• Opposing opinions: appeal (see CP)• Any changes: similar procedure
![Page 34: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/34.jpg)
3434
Mutual recognition• (When the MA has already been issued in
one MS)• The Firm requests an AR (in English) from
the national competent authority (it is the RMS then)
• It, together with the full documentation submitted to CMSs asking a „recognition” of the AR (time-frames!)
• Opposing opinions: appeal (see CP, the decision is binding)
• Any changes: similar procedure
![Page 35: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/35.jpg)
3535
EU registration collaborations
• Many Working Groups and Committees under EMEA and Commission
• EMEA CHMP Q, S, E, Herbal Medicines, Pharmacovigilance, Heads of Agencies, etc. Working Parties
• Commission Pharmaceutical Committee
![Page 36: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/36.jpg)
36
Back to the general regulatory affairs concerning registered
drugs on the market
![Page 37: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/37.jpg)
3737
Post-marketing surveillance
• GMP (manufacturers), GDP (wholesalers), GCP (CT sites), GLP (safety study laboratories)
• Drug Adverse effect monitoring (Pharmacovigilance)
• Mandatory Quality defect reporting national system
![Page 38: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/38.jpg)
3838
Pharmacovigilance
Doctors and Marketing Authorisation Holders must report (to the DRA)
• serious• unexpected (not listed in the information for
professionals)
side effects (=adverse drug reactions, ADRs),
level of seriousness, time-frames may be specified in the law
![Page 39: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/39.jpg)
39
A little story: what happens to these ADR reports?
• ADR Data Banks at national, regional (e.g. European Union) and global (e.g. WHO ADR Monitoring Centre in Uppsala, Sweden)
• All ADR data put into the Banks• From time-to-time, professionals review similar
data• If the connection between taking a drug and the
ADR is possible: it is called a signalsignal and national ADR centres, professional societies, etc. signalised: monitor this ADRs of this drug strictly
• If the connection becomes proven (many cases!): it comes to the information material of the drug
![Page 40: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/40.jpg)
40
A signal generation story (WHO Uppsala Monitoring Centre)
• Spontaneous reports ot the Data Bank• Data „mining” with softwares• Signal generation review • If causality probable: signal message to
the National Monitoring Centres• If proven later: part of the information
material of that drug
![Page 41: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/41.jpg)
41
Signal to the hydroalcoholic extract of a medicinal plant:
Teucrium chamaedrys
![Page 42: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/42.jpg)
42
Signal generation example 1
• Teucrium chamaedrys: the hydroalcoholic (alcohol-water) extracts of the herb are extremely bitter. It is frequent component of reductant (anti-obesity) tees
• There were more than 20 data on hepatic adverse reactions (jaundice, hepatitis) in the WHO database
• In cases when the patients, after recovery, drank the tee again, the same symptoms were recurring very quickly (in 2 days, the note at the registration was: rarely possible!)
![Page 43: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/43.jpg)
43
Signal generation example 2
• How to start the review?• If the quick recurrence is true, that would mean
an immunological mechanism• Literature search: can liver damage be caused
via immunological mechanism? • Answer: yes!• Literature search: the main components of the
plant are diterpenoids and fenyl-ethanoid glycosides, they are free radical scavengers
![Page 44: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/44.jpg)
44
Signal generation example 3• But these are small molecules, too small for an
immune response. Could they modify human proteins by binding on them? (E.g. an alkylating mechanism)?
• Literature search: – the tsructure of the plant components: there is no
alkílating agent among them– but, if free radical scavengers, they perhaps will be
metabolised via oxidation• Literature search: what could be oxidised
metabolites of these components? There is a furane ring on the side chain of one of the triterpenoids (the tecurin-A)
![Page 45: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/45.jpg)
45
Signal generation example 4
• Literature search: the oxidative metabolism of the furane ring is:
• Irodalmazás: this epoxid can alkylate the human epoxid hydrolase enzyme, the resulting modified protein is „foreign”, there will be antibody formation against it…
O
CYP450
OO
![Page 46: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/46.jpg)
46
Signal generation example 5• But the extracts of the plant are widely used in various products
as amarum. If this is the basis of the adverse effect, why is it so rare?
• The place of oxidative metabolisms is the liver. Perhaps is there something in the liver to react with the epoxide, other that the mentioned enzyme?
• Literature search: the epoxidesaz epoxidok prefer reaction with „soft” (according to the Pearson classification) nucleofils
• Is there such compound in the liver? Yes! The
γ-L-glutamyl-L-cysteinil-glycin (glutathion)
-HN-CH-CO-NH-
CH2-SH
![Page 47: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/47.jpg)
47
Signal generation example 6
• Now we already know why only the anti-obesity tees caused the (relatively high number of the) adverse effects
• Glutathion: extreme diurnal changes in the organism! When fasting, its level goes almost to zero! And people whi take anti-obesity tees are fasting…
• The signal is ready!WHO Signal, March 2006, pp. 8-17
![Page 48: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/48.jpg)
4848
National mandatory quality defect reporting system
• Wholesalers, marketing authorisation holders must report to the DRA drug quality defects, pharmacies even suspected ones
• Prerequisite: at least organoleptic checking of incoming drugs mandatory
![Page 49: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/49.jpg)
4949
You may say that no quality defect can never be identified
by organoleptic checking – is it true?
![Page 50: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/50.jpg)
5050
„the same” tablets in the same package unit
![Page 51: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/51.jpg)
5151
„the same” coated tablets
![Page 52: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/52.jpg)
5252
One ointment, if check the inside…
![Page 53: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/53.jpg)
5353
the same ointment
![Page 54: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/54.jpg)
5454
Drug assessment for registration:
multidisciplinary business!
![Page 55: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/55.jpg)
5555
There is sThere is still a big mistake!till a big mistake!
• In certain Universities it is presumed that assessment of medicines can be taught by simply teaching chemistry, analysis, technology, pharmacology, some clinical sciences, etc.
• That is not true! That is not true!
![Page 56: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/56.jpg)
5656
Big mistake!Big mistake!
Medicine evaluation means the recognition of the links between data generated under different scientific disciplines
![Page 57: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/57.jpg)
5757
Big mistake!Big mistake!• E.g. if a medicine (registration
application) is evaluated by chemists, analysts, pharmacists, pharmaco-logists/toxicologists and clinicians separately, this a wrong evaluation!
• It is also the message of the EU Directive!
![Page 58: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/58.jpg)
5858
Examples to indicate the spirit Examples to indicate the spirit of interdisciplinary medicine of interdisciplinary medicine
evaluationevaluation
Naturally, this topic can not be covered in a few minutes. However, it may be indicated by a few examples
![Page 59: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/59.jpg)
5959
Penicillin powder for injection in Penicillin powder for injection in vialsvials
• Quality Dossier: water content not more than 2.5 % — what shall I check during evaluation of this medicine?
• As a requirement per se : may be acceptable
• The anal. method (not Karl Fischer) seems to be O.K.
• However, a good assessor tends to be anxious to check:
![Page 60: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/60.jpg)
6060
Penicillin powder for injection in vials - topics to check
The main decomposition route is hydrolysis• Water content in the samples for stability
studies (much less than 2.5 %?)
• Water content in clinical trial samples (the
same question, for the sensitisation potential of decomposition products, chiefly the penicillin-polymers is higher)
![Page 61: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/61.jpg)
6161
Penicillin powder for injection in vials, 2
• By the way, is there any data in the clinical trial reports about the time between reconstitution of the injection solution and the administration (hydrolysis! Was it required
to use the solutions within a specified time?)• Was the decomposition rate after
reconstitution determined? And its temperature dependence?) (If not, can I
evaluate the clinical safety at all?)
![Page 62: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/62.jpg)
6262
Penicillin powder for injection in vials, 3
• Is there anything in the SmPC about the quick use after reconstitution?
• Is this issue addressed when the possibility of administration after mixing with a slow infusion is discussed from the medical point of view?
![Page 63: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/63.jpg)
6363
Next example: CYPNext example: CYP450450
metabolism, 2metabolism, 2• Is the interaction issue reflected in
the clinical trial plans? (was the concomitant medication studied, or was it “carefully avoided”? Oxydator-phenotype classification of trial subjects? Patient exposure high enough?)
![Page 64: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/64.jpg)
6464
Next example: CYPNext example: CYP450450
metabolism, 3metabolism, 3• Does the SmPC and the PIL reflect
the significance of the issue and the clinical data?
• By the way, let us go back to the chemical part and check whether the whole issue was reflected in the purity (related substances qualification) part
![Page 65: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/65.jpg)
6565
CYP450 metabolism… 4
CH3–CH2-O
NH-C-CH3
O
NH-C-CH3
O
Cl
fenacetin intermedier-product: p-chloro-acetanilid
![Page 66: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/66.jpg)
6666
CYP450 metabolism, 5
CH3–CH2-O
NH-C-CH3
O
NH-C-CH3
O
Cl
fenacetin intermedier-product: p-chloro-acetanilid
CH3–CH-O CH3–CH2-O
OH
NH-C-CH3
O
N-C-CH3
OHO
fenacetin CYP450 metabolism
![Page 67: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/67.jpg)
6767
How to facilitate the multidisciplinary drug
assessmentElectronic submissions!
![Page 68: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/68.jpg)
6868
Importance of electronic submissions
• Huge paper submissions
vs. a few CD - handling, archiving, etc...
this is true. PLUSPLUS:
• EU procedures: more fast-track recognition than assessment!
![Page 69: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/69.jpg)
6969
Paper submission:
330,000pages per
application
![Page 70: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/70.jpg)
7070
Electronic submissions for registration
Past:
Present/future:
![Page 71: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/71.jpg)
7171
Electronic applications
1000 - 3000 hyperlinks connect the related text parts of chemical - pharmaceutical - preclinical - clinical - SmPC/PIL etc.
![Page 72: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/72.jpg)
7272
Electronic dossier assessment: navigation, 1
METABOLISM: Expert Report: CYP450 interaction possibilitiesCYP450 interaction possibilities
Preclin. Dossier?
Clin. Expert Report?
Clin. Dossier, CT Protocol design?
CT results
SmPC?
SmPC: expiry date/ expiry date/ spec. Storagespec. Storage
Ch/Ph Expert Report
Ch/Ph Dossier, Stability results, statistical CI
![Page 73: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/73.jpg)
7373
Electronic dossier as-sesment: navigation, 2
Ch/Ph Dossier: Impurity ProfileImpurity Profile
Ch/Ph Expert Report
Tox. Expert Report (discusseddiscussed?)
Tox. Dossier (same profilesame profile?)
Clin. Dossier (same profilesame profile?)
![Page 74: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/74.jpg)
7474
The Essence of Hyperlinking
“If Regulatory Affairs comprise an art of recognising If Regulatory Affairs comprise an art of recognising interdisciplinary relations when reviewing dossiers, interdisciplinary relations when reviewing dossiers, hyperlinks may be taken as ‘Materialization’ of hyperlinks may be taken as ‘Materialization’ of these interdisciplinary relationsthese interdisciplinary relations” TLP, 1998
(Quoted in: Witzel et al.: Damos Experience Report, Lorenz GmbH, Frankfurt, 1998)
![Page 75: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/75.jpg)
7575
Different hyperlinking needs: review structure
External or internal
assessors?
C’ttee/Peer review?
Rapporteurs?
Or concrete Q/A’s to/from experts?
Quality assessment connected to laboratory analyses?
REVIEW SOFTWARE INTRANET?
![Page 76: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/76.jpg)
7676
Different hyperlinking needs: DRA structure
Highly specialised review
units (e.g., Quality, GMP,
Toxicology, Pharmacology,
Clinical, SPC/PIL,
Registration sections)
or
more concentrated expertise (such as Qua-lity, GMP, Biomedical and Registration)?
![Page 77: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/77.jpg)
7777
The next registration issue
We are living in a World where the human beings are the same everywhere!
Why do not we collaborate in drug registration?
![Page 78: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/78.jpg)
7878
Drug registration: an international business
• It became as international as the drug development
• Apart from the European Union where the system of Community medicine registration exists, there are many related international collaborations
![Page 79: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/79.jpg)
7979
Content
• Why collaboration?
• Why regional collaboration?
• Which collaboration technique to be chosen?
![Page 80: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/80.jpg)
8080
Content
• Why collaboration?• Why regional collaboration?
• Which collaboration technique to be chosen?
![Page 81: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/81.jpg)
8181
“Every State is responsible for its public health issues” -
why collaboration?
![Page 82: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/82.jpg)
8282
Fact:
Drug development became an international business
![Page 83: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/83.jpg)
8383
Medicine development is a global business...
![Page 84: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/84.jpg)
8484
To answer this challenge, DRAs should also go beyond frontiers (They
are doing so!)• GMP, GLP, GCP inspections over the
globe? Or information sharing (e.g. WHO
Certification Scheme…)recognition? (If you do not require such data, this is recognition without information! )
• Information on foreign drug/CT app-rovals/rejections (Are you not interest-ed?)
• PhV (Are you satisfied with your country’s reports, if any, alone?)
![Page 85: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/85.jpg)
8585
Next argument
• Is Q-S-E assessment based on science? YES
• Is science international? YES
• Then?
![Page 86: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/86.jpg)
8686
Next argument• Drugs are for patients to cure diseases
• Are patients and diseases different in different countries?
• ICH assessment: mostly not, in a few per cent yes
• Exaggerated! Pharmacogenetic and pharmacokinetic differences in the same population
![Page 87: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/87.jpg)
8787
Concrete example (Drug Y)
• No pharmacokinetic differences between Caucasian, Japanese and Black races
• Combined effects of gender, age smoking within the same race: the Creatinine Clearence in young smoking males 3 times higher than that in elderly non-smoking females
B.K. Malhotra, 2001
![Page 88: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/88.jpg)
8888
Further argument
• If new medicines of proven high efficacy appear, is there a public health interest to make them available as soon as possible?
• It were very difficult to answer “no”!
• But let us discuss it in more detail, it is a hot topic!
![Page 89: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/89.jpg)
8989
Thus, all DRAs benefit the international collaboration when
registering drugs...
…by using/taking into account• literature data• foreign DRA decisions (e.g. WHO channel)• foreign registration and GMP certificates (e.g.
WHO Certification Scheme…)• foreign PhV data
in a non-structured way!
![Page 90: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/90.jpg)
9090
Entering into collaboration
The national DRA will have access to these and even more data/information in a structured way!
![Page 91: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/91.jpg)
9191
Content
• Why collaboration?
• Why regional collaboration?• Which collaboration technique to be
chosen?
![Page 92: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/92.jpg)
9292
Why regional collaboration,1
Sometimes: all DRAs did it before!
See countries before splitting into new States
![Page 93: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/93.jpg)
9393
Why regional collaboration, 2
Many do exist successfully!
1999 Geneva WHO/CIOMS Meeting on Regional Harmonisation: many identified
• Latin America (at least 2)• Africa• Middle East• South-East Asia...
![Page 94: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/94.jpg)
9494
Changing drug selection, medical practice...
……problems not experienced elsewhereproblems not experienced elsewhere
• Hungarian example: the antipyretic aminophenazone shifted to paracetamol, resulting in a “few” deaths due to intoxication
• the same rapid action expected by patients/parents
• high alcohol consumption in Hungary
![Page 95: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/95.jpg)
9595
Benefits of a regional collaboration
Apart from the psychological factor, should every country repeat evaluations (QC analyses, CTs, etc.) done in another country?
![Page 96: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/96.jpg)
9696
Regional collaboration- counter-arguments
“We are more clever (knowledgeable, professional, etc.) than those in another countries”
(No comment!)
![Page 97: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/97.jpg)
9797
Regional collaboration- counter-arguments
(The psychological factor)
The Hungarian ice-hockey team example
(Who would be the leader?)
![Page 98: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/98.jpg)
9898
Regional collaboration - counter-arguments
Too many collaborations!
• Financing
• Time
(However - see benefits - the more the DRA can afford it the more benefits, also saving resources, are gained! See CADREAC, PERF...)
![Page 99: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/99.jpg)
9999
Content
• Why collaboration?
• Why regional collaboration?
• Which collaboration technique to be chosen?
![Page 100: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/100.jpg)
100100
Collaboration techniques, examples, evaluation
• Supranational as EU. General. “Forced” collaboration, limited sovereignty, i.e. Community Procedures, etc. It would be more than premature for SEE.
• Global technical, see ICH. Surely not a SEE goal
![Page 101: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/101.jpg)
101101
Collaboration techniques, examples, evaluation (cont’d)
• Mandatory special such as former EFTA Conventions like PIC (GMP), or OECD (GLP), or Eu.Pharm. Mandatory recognition in special areas. Not worth-wile and may not be acceptable
![Page 102: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/102.jpg)
102102
Collaboration techniques, examples, evaluation (cont’d)
• Not mandatory but information and expertise-sharing such as EFTA Schemes (e.g. Pharmaceutical Evaluation Report Scheme, PER). Shared info on registered medicines and the results of the evaluation, arguments for acceptance-rejection, common guidelines, etc. Consider it!
![Page 103: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/103.jpg)
103103
How to build up a regional collaboration, 1
• Common meetings. Will needed
• Agreement between DRAs, it communicated to industry
• Start with info sharing ondrugs registered/refused, reason
CTs authorised refused, reason
Laws/regulations/guidelines issued
Implementation experiences, problems
Still nothing mandatory
![Page 104: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/104.jpg)
104104
How to build up a regional collaboration, 2
If it works:
• Extension to collaborative development of
technical guidelines
procedural guidance
![Page 105: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/105.jpg)
105105
How to build up a regional collaboration, 3
If it works, extension to
• Common drug evaluation
personnel changes, study tours
participation in each other’s drug evaluation
joint inspection teams
Still nothing is mandatory!
![Page 106: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/106.jpg)
106106
How to build up a regional collaboration, 4
If it works, possible extension to
• Mutual recognition” (in the EU meaning) of marketing authorisation, inspections
still retaining the ultimate national responsibility for decision!
STEPWISE APPROACH, EXISTING FORMS, NO LEGAL OBLIGATION, IT WOULD BE WORTH OF TRYING!
![Page 107: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/107.jpg)
107107
Hungarian international drug registration collaborations
• European Pharmacopoeia• Pharmaceutical Inspection Cooperation
Scheme (PIC-S)• OECD GLP Working Party...• WHO International Pharmacopoeia,
guidelines…• European Union…
![Page 108: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/108.jpg)
108
Exam topic
![Page 109: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/109.jpg)
109
Registration of drugs
• Different kinds of drug authorisations for use: the 3 levels according to WHO
• Medicine use possibilities, other than registered ones• Registration as product characterisation plus legal and
professional sides• The 3 main elements of the professional side• Characterisation of the content of an application (CTD)• The flow of the registration process of a new drug• The CJD issue• Prescription statuses, their reason, switches between these
statuses• Accompanying info for professionals and patients• Deletion from the register versus batch recall
![Page 110: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/110.jpg)
110
Registration of generics and the European Union marketing
authorisation routes• Description of the application types (from fill
application to generics)• Patent protection and data exclusivity• Doha declaration• What is a generic drug. Ho9w to establish
equivalence• Discuss the EU Community procedures (3) in
short• The European Medicines Agency• International (global and regional) registration
collaborations
![Page 111: 11 Prescription (legal) status Categories vary country by country NP („OTC”) POM Subcategories Prescription](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e235503460f94b11130/html5/thumbnails/111.jpg)
111
Levels of proof for the use of drugs
• List the levels of proof and their order
• Explain the clinical terminology